PB2278: ACQUIRED ANGIOEDEMA ASSOCIATED WITH LYMPHOPROLIFERATIVE DISORDERS: A CASE SERIES
Authors: Jun Yen Ng, Meidelynn Ooi, Samuel Bennett, Kirsty Rady, Philip Choi, Wei-I Lee, Matthew Cook, Katrina Randall, Nalini Pati
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Acquired angioedema due to C1 esterase inhibitor deficiency (C1INH-AAE) is most associated with lymphoproliferative disorders (LPD) particularly low-grade B-LPD However, this diagnosis may be challenging. A recent study reported a median diagnostic delay of 1.1 (0.5-2.6) years from onset of angioedema. Possible reasons are lack of awareness of the condition, misdiagnosis of the angioedema symptoms as part of the hematologic disorder. Aims: We discuss 4 cases of C1INH-AAE associated with low-grade B-LPD including the diagnostic challenges and management. Methods: Case series Results: Four patients presented with angioedema affecting different organs without constitutional symptoms, lymphocytosis, cytopenia or significant lymphadenopathy. These patients were males between the 53-79 years of age. C1INH-AAE was diagnosed based on complement C4, C1INH level and function. Bone marrow examination (BME) confirmed various low-grade B-LPDs. Chemoimmunotherapy led to improvement of the angioedema both clinically and biochemically, as reflected by the complement, C1INH level and function values. C1INH-AAE should be considered in patients presenting with isolated angioedema without urticaria. It is most associated with LPD (62.8%), followed by monoclonal gammopathy of uncertain significance (27.7%), autoimmune disorders (10.6%) and solid organ tumors (5.3%). The prevalence was 10.7% in a retrospective study screening 131 patients with various LPD for complement and C1INH levels but only 2.3% experienced significant angioedema. The most associated LPD is SMZL. The postulated mechanisms of C1INH-AAE in LPD include neutralising antibodies against C1INH, and overactivation of the classical complement pathway by neoplastic lymphoid tissue. It is important to distinguish C1INH-AAE from hereditary angioedema (HAE) which tends to present before the second decade of life. Difficult cases may require genotyping for SERPING1, a heterozygous mutation only present in HAE. The laboratory diagnosis of C1INH-AAE is suggested by reduced complement C4, C1q, C1INH level and function however abnormalities may fluctuate during the clinical course. Additionally, the presence of autoantibodies to C1INH in C1INH-AAE has been known since the 1980s, but their presence can only be inferred as no commercial autoantibody assays are available. Our cases illustrate that the underlying LPD can be subtle. Recommended methods for screening for an underlying LPD include physical exam, full blood count, lactate dehydrogenase, beta-2-microglobulin, plasma urea, creatinine, serum calcium, serum protein electrophoresis, immunophenotyping of circulating lymphocytes for a monoclonal population, and CT of chest, abdomen, and pelvis. Treatment of the underlying haematological malignancy commonly leads to improvement or resolution of the AAE, both clinically and biochemically. Hence, C4, and C1INH levels and function are useful for monitoring disease progress. Changes in these parameters or recurrence of angioedema may indicate relapse of underlying haematological malignancy. There are no treatments registered or approved for C1INH-AAE, however treatments for HAE (e.g., C1INH concentrate, the bradykinin-receptor antagonist icatibant) have demonstrated efficacy. Rituximab, an anti-CD20 monoclonal antibody has also been shown to be effective in patients with or without underlying B-LPD. Summary/Conclusion: Awareness of C1INH-AAE can lead to an early diagnosis of haematological malignancies. The absence of constitutional symptoms associated with LPD emphasizes the need for a comprehensive multimodal approach to the screening of LPD in C1INH-AAE. Complement C4 and C1INH levels and function are useful for monitoring the activity of C1INH-AAE. Keywords: Splenic marginal zone lymphoma